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A male neonate weighing 2,490 g is born to a 33-year-old nonconsanguineous couple at 34 weeks of gestation by vaginal delivery. Ultrasonography performed just before delivery shows fetal pericardial effusion, ascites, polyhydramnios, and placentomegaly, with a placental thickness of 2.4 in (6 cm) and weighing 746 g. These findings are suggestive of hydrops fetalis. On review of previous reports, the 18-week scan shows no evidence of any fetal anomaly, and no reports are available after that. The mother's blood group is O positive. No other antenatal tests, including fetal middle cerebral artery Doppler for assessment of fetal anemia, or prenatal genetic testing or screening are available.The neonate is vigorous at birth, with Apgar scores of 9 and 9 at 5 and 10 minutes, respectively, but develops respiratory distress immediately after birth requiring continuous positive airway pressure support. There is anasarca with gross ascites and abdomen wall edema, further compromising respiration (Fig 1A). He is also pale, with no jaundice or cyanosis. There is no hemodynamic instability. Head circumference and length are 12.2 in (31 cm) and 17.7 in (45 cm), respectively (50th percentile as per modified Fenton chart). On detailed clinical examination, he has flat facies, antimongoloid slant, protruding tongue, bilateral simian crease, and hyperextensible joints. There are extensive petechiae noted all over the body (Fig 1B). There is hepatosplenomegaly, with the liver palpable 1.6 in (4 cm) below the right costal margin firm with a nonpalpable left lobe. The spleen is palpable 1.2 in (3 cm) below the left costal margin. Central nervous system examination shows a depressed sensorium with axial and appendicular hypotonia with diminished deep tendon and neonatal reflexes. Cardiovascular examination findings are normal. He is further evaluated for nonimmune hydrops with hepatosplenomegaly, petechiae, and dysmorphism.Chromosomal abnormalities +/– systemic manifestations: trisomy 21, trisomy 18, and monosomy XStorage disorder: lysosomal storage disorderMalignancy: congenital leukemia, transient myeloproliferative disorderAn emergency ascitic fluid tap is performed in the delivery room, and 25 mL of transudative fluid is removed. After the therapeutic tap, there is an improvement in respiratory distress. The neonate is shifted to the NICU for further management, and the investigations performed are summarized in Table 1.Considering the presence of 15% blast cells in the bone marrow examination in the background of nonimmune hydrops and karyotyping suggestive of trisomy 21, a diagnosis of transient abnormal myelopoiesis (TAM) of Down syndrome (DS) is made. Fluorescence in situ hybridization for further confirmation of GATA1 and PTPN11 mutations are positive.Nonimmune hydrops secondary to TAM (GATA1 and PTPN11 mutation) of DSHe is continued on continuous positive airway pressure support, and milk feeds are given as gavage feeds. A multidisciplinary team consisting of a hematologist, a geneticist, a cardiologist, an occupational therapist, a clinical psychologist, and a social worker are involved in the management. Parents are counseled about the disease, and chemotherapy is initiated with intravenous cytarabine (2 mg once a day for 5 days). During the therapy, the neonate develops sepsis and thrombocytopenia, which are managed with intravenous antibiotics and platelet transfusion. He is monitored for tumor lysis syndrome. No other complications are noted and, after chemotherapy, there is complete remission. Investigations performed during the chemotherapy are summarized in Table 2.Respiratory support is weaned by day 7 after birth. He is gradually transitioned to oral feeds and then breastfeeds by age 30 days and is discharged on day 40 with a weight of 2,800 g. Multidisciplinary team counseling, including genetic counseling, is offered to the parents, highlighting the need for regular follow-up for DS and TAM. The infant is currently 8 months old (Fig 1C) and is on regular follow-up. The details of investigations performed during follow-up are summarized in Table 2. There is no relapse or complications related to TAM. He continues to receive early intervention, with improved hypotonia with normal cognition, language, vision, hearing, and growth.TAM is characterized by GATA1 mutation with anemia, leukocytosis with/without thrombocytopenia, and more than 10% blast cells on a peripheral smear. (1) The current incidence of TAM in DS is 10%, with fetal anemia and hepatic dysfunction causing hydrops fetalis in 90.9% and 28%, respectively. Approximately 39 antenatal cases of TAM have been reported worldwide, with 13 patients (33.3%) presenting with hydrops fetalis and hepatomegaly, of which 12 (92.3%) died either prenatally or in the early neonatal period. (2) Postulates suggest the interplay of DS, GATA1, and the presence of additional oncogenic mutations to be responsible for the evolution of TAM. GATA1 mutation promotes the selective proliferation of dysmegakaryopoietic cells in the fetal liver, which in the presence of DS is further aggravated, leading to a higher risk of hepatosplenomegaly, heart failure, and stillbirth. (2) The pathogenesis of HF in this condition is likely to be multifactorial. In this patient, fetal anemia seemed to be the main etiologic factor, with other possible contributory mechanisms such as local hypoxia secondary to leukocytosis and capillary damage. This emphasizes the importance of diagnosing TAM antenatally and screening for features of DS and associated complications in these fetuses for early recognition of HF; however, there is no definitive prenatal treatment, with interventions such as intrauterine blood transfusion being tried with no proven benefit. (3)TAM can be an incidental finding (silent TAM) or can present with widespread dissemination, causing hepatosplenomegaly, pleural effusion, coagulopathy, and multiorgan failure. (4) Cases presenting antenatally with HF or postnatally developing hepatic encephalopathy and coagulopathy carry an increased risk of mortality of up to 100%. (5) Most neonates with silent TAM undergo spontaneous remission; however, those with HF, leukocytosis (white blood cell count >100,000/µL >100 × 109/L), hepatopathy, coagulopathy, or renal or cardiac failure may benefit from cytarabine chemotherapy at a dose of 0.5 to 1.5 mg/kg intravenously for 3 to 12 days. (4)(6) In our patient, these morbidities were addressed and complications were prevented by early management of HF with a therapeutic tap of ascites in the delivery room, early diagnosis on peripheral smear, GATA1 mutation testing and monitoring of liver function tests, and early initiation of cytarabine injection.Cytarabine is a pyrimidine analogue preventing the replication of DNA in the S phase of the cell cycle. However, the evidence of its effect on the progression of TAM to myeloid leukemia of DS is limited. (6) As in the index neonate, it is prudent to confirm GATA1 and PTPN11 mutations by direct Sangers sequencing because these infants with GATA1 mutation are at 10% to 20% higher risk for myeloid leukemia of DS, (1) thus requiring a well-structured follow-up for early diagnosis and management of myeloid leukemia of DS in addition to the comorbidities associated with DS.In the case of antenatal heart failure, there should be a high index of suspicion of transient abnormal myelopoiesis (TAM) and its association with Down syndrome (DS).Symptomatic TAM presenting as heart failure requires early initiation of chemotherapy for a better prognosis.Genetic evaluation for GATA and PTPN mutations in a suspected case of TAM with DS must be performed to predict the risk of developing myeloid leukemia of DS.Well-structured follow-up for early diagnosis of myeloid leukemia of DS and the comorbidities associated with DS help in enabling a better quality of life, growth, and neurodevelopment.The authors thank Dr Sangeeta Ravat, dean, Seth G.S. Medical College and King Edward Memorial Hospital, Mumbai, India, for granting permission for publication.
Nair et al. (Sun,) studied this question.